Abstract
Key points Auditory brainstem neurons of all vertebrates fire phase‐locked action potentials (APs) at high rates with remarkable fidelity, a process controlled by specialized anatomical and biophysical properties.This is especially true in the avian nucleus magnocellularis (NM) – the analogue of the mammalian anteroventral cochlear nucleus.In addition to high voltage‐activated potassium (KHVA) channels, we report, using whole cell physiology and modelling, that resurgent sodium current (I NaR) of sodium channels (NaV) is equally important and operates synergistically with KHVA channels to enable rapid AP firing in NM.Anatomically, we detected strong NaV1.6 expression near hearing maturation, which was less distinct during hearing development despite functional evidence of I NaR, suggesting that multiple NaV channel subtypes may contribute to I NaR.We conclude that I NaR plays an important role in regulating rapid AP firing for NM neurons, a property that may be evolutionarily conserved for functions related to similar avian and mammalian hearing. Auditory brainstem neurons are functionally primed to fire action potentials (APs) at markedly high rates in order to rapidly encode the acoustic information of sound. This specialization is critical for survival and the comprehension of behaviourally relevant communication functions, including sound localization and distinguishing speech from noise. Here, we investigated underlying ion channel mechanisms essential for high‐rate AP firing in neurons of the chicken nucleus magnocellularis (NM) – the avian analogue of bushy cells of the mammalian anteroventral cochlear nucleus. In addition to the established function of high voltage‐activated potassium channels, we found that resurgent sodium current (I NaR) plays a role in regulating rapid firing activity of late‐developing (embryonic (E) days 19–21) NM neurons. I NaR of late‐developing NM neurons showed similar properties to mammalian neurons in that its unique mechanism of an ‘open channel block state’ facilitated the recovery and increased the availability of sodium (NaV) channels after depolarization. Using a computational model of NM neurons, we demonstrated that removal of I NaR reduced high‐rate AP firing. We found weak I NaR during a prehearing period (E11–12), which transformed to resemble late‐developing I NaR properties around hearing onset (E14–16). Anatomically, we detected strong NaV1.6 expression near maturation, which became increasingly less distinct at hearing onset and prehearing periods, suggesting that multiple NaV channel subtypes may contribute to I NaR during development. We conclude that I NaR plays an important role in regulating rapid AP firing for NM neurons, a property that may be evolutionarily conserved for functions related to similar avian and mammalian hearing.
Highlights
Voltage-dependent sodium (NaV) channels play a critical role in generation of action potentials (APs), the firing pattern of which is fundamental for information processing in the nervous system (Eijkelkamp et al 2012)
By investigating the function of INaR in AP firing rates of chicken nucleus magnocellularis (NM) neurons both experimentally and computationally, we found that NM neurons have robust INaR that significantly increases NaV availability immediately after depolarization and facilitates NaV channel recovery
We examined the maturation of INaR relative to hearing onset and the potential NaV channel subtype that carries this current in developing NM using immunocytochemistry
Summary
Voltage-dependent sodium (NaV) channels play a critical role in generation of action potentials (APs), the firing pattern of which is fundamental for information processing in the nervous system (Eijkelkamp et al 2012). Activation of the open channel blocker facilitates the recovery of NaV channels after depolarization and increases NaV channel availability by competing against classic inactivation (Raman & Bean, 2001). This specific blocker has been identified as the β4-subunit in cerebellar Purkinje cells (Grieco et al 2005; Aman et al 2009), whereas multiple α-subunits (e.g. NaV1.2, 1.5, 1.6 and 1.7) have been shown to be capable of carrying INaR (Rush et al 2005; Jarecki et al 2010). As a result of unique features of the open channel blocker, studies show that INaR plays an important role in promoting high rates of AP firing in numerous mammalian neurons, underlying their highly specialized information processing patterns (Lewis & Raman, 2014)
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